Epigallocatechin gallate and thermal cycling-stimulation synergistically promote apoptosis in A549 cells via endoplasmic reticulum stress-induced calcium ion dysregulation and oxidative stress

Non-small cell lung cancer (NSCLC), as the predominant subtype of lung cancer, presents a considerable clinical challenge due to its high rates of recurrence and the significant adverse effects associated with conventional therapeutic modalities. In response to these challenges, this study explored the new combined anticancer effects of epigallocatechin gallate (EGCG) together with thermal cycling-stimulation (TCS). The findings demonstrated that the combination of EGCG and TCS synergistically decreased the viability of A549 and NCI-H460 NSCLC cells, while exhibiting minimal cytotoxic effects on IMR-90 normal lung fibroblasts. Further investigation revealed that EGCG mitigated the TCS-induced upregulation of heat shock proteins HSP70 and HSP105 and concurrently diminished the expression levels of proteasome subunits. This combined effect disrupted proteostasis, resulting in pronounced endoplasmic reticulum (ER) stress. Subsequently, a positive feedback mechanism was established between inositol 1,4,5-trisphosphate receptor (IP3R)-mediated ER Ca2+ release and excessive reactive oxygen species (ROS) production, ultimately leading the cells to undergo mitochondrial apoptosis. This combined treatment reduces the necessary dosage of EGCG, thereby overcoming limitations related to its poor bioavailability and systemic toxicity, while also preventing the development of thermotolerance induced by TCS. Consequently, this method offers a new and potentially practical therapeutic strategy for treating NSCLC.